Spinal Cord Injuries

The Current Concept for Stem Cell Therapy in Spinal Cord Injury

Spinal cord injury with neurological deficits is devastating to patients and their families. After the immediate treatment that may involve spinal decompression and stabilization surgeries, patients are typically left with long-term disability. Intense research has focused on spinal cord regeneration, tissue repair, and reinnervation to improve function. Stem cell-based therapies are at the center of this effort. This chapter summarizes common spinal cord injury (SCI) patterns, including complete and incomplete SCIs, and their classification-based prognosis and treatments. They review the types of stem cells used in preclinical and clinical trials in the treatment of SCI and the associated ethical concerns and summarize the current state of the art of stem cellbased SCI treatments.

Common Surgical Procedures in Geriatric Patients

Demographic studies show that life expectancy for people in the USA has been trending upwards for the past several decades. As the population ages, the number of geriatric patients who will require surgery has also increased. Information from the National Hospital Discharge Survey reported that in 2006, 35.3% of all inpatient procedures and 32.2% of all outpatient procedures were in patients aged 65 and older. Common elective surgeries in elderly patients include cataract and lens procedures, spinal fusions and laminectomies, and total or partial hip and knee replacements. Common urgent surgeries in this population include thoracic and abdominal cancer resections, breast and prostate cancer resections, and cholecystectomies. Finally, common emergency surgeries in the elderly population include hip fracture repairs and other geriatric traumas.

Female Geriatric Patients

Men and women are created equal, but there are some biological differences between the two sexes that should be considered in the perioperative period to provide safe and equitable care. This chapter highlights specific anatomical differences between men and women and discusses conditions by system that are more prevalent among female geriatric patients. Plus, it briefly discusses particular sex differences in the pharmacokinetics of some drugs.

Anesthetic Considerations for Patients with Chronic Neurologic Disorders

Chronic neurological disorders encompass a broad range of challenges for the surgical and anesthesiology team in the perioperative setting. According to the World Population Prospects 2019, by 2050, 1 in 6 people will be over 65, from 1 in 11 in 2019 [1]. As our population continues to age, our understanding and ability to provide medical and surgical services must improve as well. Perioperative strokes are rare, but they can greatly impact a patient's recovery and function when they occur. Dementia strongly predicts postoperative complications, higher hospital costs, and 30- day mortality [2]. Patients with Parkinson’s disease are at a higher risk of perioperative medical and surgical complications not to mention specific medication regimens that need to be adjusted to avoid worsening symptomatology. Although rare, a patient presenting with Amyotrophic lateral sclerosis (ALS), can present with a broad range of neurologic symptoms, and cardiovascular and pulmonary dysfunction that can be daunting for any anesthesia provider. In this chapter, we will explore the comprehensive approach to managing chronic neurologic disorders, including multidisciplinary care, early identification of potential complications, specialized medication management, and intraoperative considerations.

Geriatric Trauma Patient

Trauma is a leading cause of death for the geriatric population. Because of the acuity of the patient presenting in such circumstances, it is imperative to have a grasp of physiological changes that occur with time. As an anesthesia provider, understanding physiological changes can adjust the anesthetic plan, dosages, and uses of certain medications. It is also important to convey the risks and benefits of proceeding with major invasive surgery and recovery. Many patients now have living wills or advanced directives that may assist in decision-making.

Geriatric Pain Patient

Chronic pain is a major cause of physical disability, poor mental health, and decreased quality of life [1,2]. The burden of chronic pain is reflected in increased medical care utilization and consequently increased healthcare costs, which are estimated at an astounding $560 billion per year [3]. CDC estimates from 2019 reveal that while 20.4% of adults in the USA live with chronic pain, the prevalence increases with advancing age [4]. 30.8% of people aged 65 years and above had chronic pain while 11.8% of them had high-impact chronic pain, which is defined as pain that causes significant restriction of self-care, social and work-related activities [5]. The impact of chronic pain is more severe in the elderly; older adults report poorer physical health and disability in comparison to younger adults [6-8]. Chronic pain in the elderly is also associated with poorer sleep, cognitive decline, dementia, and death [9-13]. With the projected increase in the elderly population in the US every year, the burden of chronic pain is only expected to increase. This chapter outlines the physiologic and pharmacologic changes that happen with ageing, the major causes of chronic pain in the elderly, as well as the myriad of treatment options available with a focus on pharmacotherapy, behavioral and alternative therapies, and interventional pain therapies. The focus of treatment is not only targeted towards reducing pain but special considerations should be made to minimize the cognitive effects of polypharmacy in light of multiple comorbidities and promote mental well-being and functional independence [14].

Anatomical and Physiological Changes in Aging

The human body is a complex connection of various systems, each affected by the internal and external environment. Each system relies on the other and changes in one can result in variations in all other organ systems. As humans age, their physical appearance changes, but the aging process also occurs below the skin. Each organ system is impacted by time, and an individual’s lifestyle can greatly impact his/her organ system. Various anatomical and physiological alterations that occur to the major organ systems due to aging and are relevant to an anesthesiologist are discussed below.

Defining the Moral Status of an Embryo? Or Defying the Moral Status of a Woman?

Embryonic Stem Cells (ESC) are pluripotent cells that give rise to all cell types and are used for cell replacement and regenerative therapies. However, ethical, social, and legal controversies have questioned the morality of the procedures to obtain ESC lines, and the moral status of an embryo is oscillating in the debate about the origin of life, whether it originates at the totipotent stage or at the point of syngamy. Ironically, the moral status of women is also being defied by inadequate informed consent for medical procedures and their life-threatening consequences. In response to the ESC controversy, an alternate approach of using low-grade embryos for obtaining ESC lines has been proposed. This study aims to define the moral status of an embryo, question the defined status of a woman, and find new ethical-based medical procedures to obtain ESC lines.

Morphine

Morphine is a Schedule II drug and it is used in pain treatment. Like other opioid drugs, it also has addictive properties. The other street names of Morphine include M, Miss Emma, Monkey, Roxanol, and White Stuff. There are natural alkaloids come from the resin of opium poppy, Papaver somniferum. Morphine is attached to the receptors in the brain and spinal cord to block pain signals. Morphine impacts the level of dopamine and serotonin by acting in the brain's reward system. Breathing and heart rate are also modified due to morphine which has both short-term and long-term effects. Morphine can last up to 4 to 6 hours in blood. It also acts on the dendrites and spines in order to change the plasticity of the neurons. Endogenous and exogenous opiates target the same tissues and cells.

Subject Index

Inflammasomes, Inflammation and Neuropathic Pain

Inflammasomes such as NOD-like receptor protein 1 (NLRP1), NLRP3, NLR family CARD domain-containing protein 4 (NLRC4) and absent in melanoma 2 (AIM2) are the primary mediators of inflammation and its associated neuropathic pain. These inflammasomes are activated leading to various autoimmune & metabolic disorders, cancer, and other inflammatory diseases. The activation of inflammasomes occurs due to molecular alterations like mitochondrial dysfunction, neuroinflammation, lysosomal damage, oxidative stress, sensitization, and disinhibition, which lead to proinflammatory pathways causing inflammasome-related neuropathic pain. Among these inflammasomes, NLRP3 has been widely studied and proven to be the key player in the development of neuropathy. In this chapter, we have summarized the role of inflammasome and how NLRP3 is involved in neuropathic pain. Therefore, based on the facts available, it has been suggested that focusing on inflammasome activity may be a cutting-edge and successful treatment approach for neuropathic pain.

The NLRP3 Inflammasome as a Target for Antiinflammatory Drugs

The Nod-like receptor protein 3 (NLRP3) inflammasome plays a vital role in the nonspecific immune response to inflammatory triggers such as cellular infections, injury, or stressors, and it has also been associated with several inflammation-related diseases. NLRP3 inflammasome activation results in the production of proinflammatory cytokines, contributing to an increased risk of inflammatory conditions, such as cardiovascular, metabolic, infectious, and neurodegenerative diseases. Several signaling pathways and cellular events involved in the NLRP3 inflammasome assembly and activation have been studied, and inhibitory mechanisms have been identified. NLRP3 inflammasome inhibition decreases inflammation and inflammasome-mediated cell death. In prospecting for novel anti-inflammatory therapeutics, signaling molecules upstream or downstream on the NLRP3 inflammasome pathway can serve as viable drug targets. Effective inhibition of these molecules culminates in the downregulation of the expression of proinflammatory cytokines like interleukin-1beta (IL-1β) and IL-18. This chapter elucidates the various classes of NLRP3 inflammasome inhibitors, their resultant anti-inflammatory effects, and various mechanisms of action.

Natural Products as a Therapeutic Approach in Regulating Autophagy for the Management of Neurodegenerative Diseases

Autophagy is a complex phenomenon that occurs constantly in cells for maintaining the well-being of individuals. However, any dysregulation in the mechanism or the proteins involved leads to detrimental effects on several diseases including cancer, diabetes, and neurodegenerative diseases (NDs). Autophagy dysfunction is involved in the progression of NDs including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). With the involvement being identified, autophagy has become a prospective target in ameliorating NDs. Natural products in the form of extracts and bioactive compounds were repeatedly reported for targeting autophagy-related proteins and the mechanism making them promising drug candidates against NDs. The current chapter briefly outlines the role of autophagy in NDs and the effect of selected natural products in restoring pathological outcomes.

Role of Gut Microbiota in Neuroinflammation and Neurological Disorders

The prevalence of neurological diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Multiple sclerosis (MS) are growing in the world, but their pathogenesis is unclear and effective treatment does not exist. Neuroinflammation is associated with many neurodegenerative mechanisms involved in neurodegenerative diseases. The human gut microbiota is an aggregate of microorganisms that live in the gastrointestinal tract (GIT) that plays a crucial role in maintaining human health and the pathogenesis disease condition. The microbiota can affect neuronal function through neurotransmitters, vitamins, and neuroactive microbial metabolites like shortchain fatty acids. The change in gut microbiota architecture causes increased permeability of the intestine and immune system activation, contributing to systemic inflammation, neurological injury, and eventually neurodegeneration. Available data suggest that the microbiota send signals to the central nervous system (CNS) by activating afferent neurons of the vagus nerve via neuroendocrine and neuroimmune pathways. The molecular interaction between the gut/microbiome and CNS is complex and bidirectional, ensuring gut homeostasis and proper digestion. Evidence suggests that dysfunction of the gut-brain axis could be a significant factor leading to many disorders of CNS. In this chapter, we explore how the gut microbiome may affect brain function and the development of neurological disorders. In addition, we are also trying to highlight the recent advances in improving neurological disease by supplemental probiotics and faecal microbiota transplantation via the concept of the gut-brain axis to combat brain-related dysfunction.

Recent Drugs Tested in Clinical Trials for Alzheimer´s and Parkinson´s Diseases Treatment: Current Approaches in Tracking New Drugs

Affecting more than 50 million people worldwide and with high global costs annually, neurological disorders such as Alzheimer's disease (AD) and Parkinson’s disease (PD) are a growing challenge all over the world. Globally, only in 2018, AD costs reached an astonishing $ 1 trillion and, since the annual costs of AD are rapidly increasing, the projections estimate that these numbers will double by 2030. Considering the industrial perspective, the costs related to the development of new drugs are extremely high when compared to the expected financial return. One of the aggravating factors is the exorbitant values for the synthesis of chemical compounds, hindering the process of searching for new drug candidates. In the last 10-year period, an average of 20 to 40 new drugs were approved per year, representing a success rate of less than 6%. However, the number of referrals for new drug orders and/or applications remained at approximately 700 each year, reinforcing the difficulty in the process of identifying and developing novel drugs. Regarding neurodegenerative diseases, the FDA (USA) approved 53 new therapies in 2019, including 48 new molecules and, from these, three are medicines and two are vaccines. The main drugs recommended for the treatment of these disorders are included in the following classes: Dopamine supplement (Levodopa), Monoamine oxidase (MAO) inhibitor (Selegiline, Rasagiline), Dopamine agonist (Apomorphine, Pramipexole), and Acetylcholinesterase inhibitor (Donepezil, Rivastigmine, Galantamine). Additionally, the current pharmacological treatments are not able to cure these patients and considering the etiological complexity and the prevalence of neurological disorders, scientists have a great challenge in exploring new therapies and new molecules to find an adequate and viable treatment for these diseases. Clinical trials are essential in this process and thus, this chapter describes the most important drugs that were targets of phase III and IV clinical studies in the last five years, associated with the most common neurological disorders worldwide, AD and PD. Information about mechanisms of action, experimental studies in other diseases that support their use, and chemical structure of the drugs are included in this chapter. Additionally, nature as a source of valuable chemical entities for PD and AD therapeutics was also revised, as well as future advances in the field regarding tracking new drugs to get successful results and critical opinions in the research and clinical investigation.

Subject Index

Biomaterials and Mesenchymal Stem Cells

Mesenchymal stem/stromal cells are splendid cell sources for tissue engineering and regenerative medicine attributed to the unique hematopoietic-support and immunomodulatory properties as well as the multi-dimensional differentiation potential towards adipocytes, osteoblasts, and chondrocytes in vitro and in vivo. To date, MSCs have been identified from various approaches, such as perinatal tissues, and adult tissues, and even derived from human pluripotent stem cells (hPSCs). Longitudinal studies have indicated the ameliorative effect and therapeutic efficacy upon a variety of refractory and recurrent disorders such as acute-on-chronic liver failure (ACLF), acute myeloid leukemia (ACLF), premature ovarian failure (POF), and intractable wounds. To date, MSCs have been a to have various origins, including mesoderm, endoderm and ectoderm. In this chapter, we mainly focus on the concepts, and biological and therapeutic properties of MSCs, together with the standardizations for industrial transformation. Overall, the descriptions would help promote a better understanding of MSCs in disease pathogenesis and management and benefit the preclinical and clinical applications in the future.

Neural Stem Cells in Tissue Engineering

Neural stem cells (NSCs) are unique subsets of stem cells with self-renewal and multiple lineage differentiation potential, which are considered promising cell sources for neuron generation and complex cognitive and sensory functions, and the resultant NSC-based cryotherapy for regenerative purposes. Of them, distinguished from the small amount of activated subset, most of the NSCs are maintained in the quiescent state and reveal a low level of metabolic activity but a high sensitivity to the environment. The dynamic balance between quiescence and the activity of NSCs determines both the efficiency of neurogenesis and the long-term maintenance and self-renewal of the NSC pool as well as the neurogenic capacity of the brain. In this chapter, we mainly review the classification and biofunction of NSCs, and introduce the significant progress in the understanding of NSC-based applications and the underlying molecular mechanism for NSC quiescence, the dysfunction in neurogenesis, and the pathogenesis of neurological disorders. Collectively, these data will facilitate the development of NSC-based cytotherapy for a broad spectrum of refractory and recurrent diseases in the future.

Biomaterials and Stem Cells

Longitudinal studies have indicated the involvement and performance of multitudinous biomaterials for stem cell-based cytotherapy and regenerative medicine largely attribute to their specific biocompatibility. Currently, stem cells and biomaterial scaffolds have been considered as the two essential elements of the cornerstone of tissue engineering. On the one hand, biomaterials are beneficial to provide suitable microenvironments for enhancing the cellular vitality and therapeutic effect of stem cells. On the other hand, biomaterial-induced fibrosis and inflammation remain a prominent challenge in designing and synthesizing appropriate materials to facilitate tissue repair and organ regeneration. In this book chapter, we summarize the classification and physicochemical properties of the indicated biomaterials, and appraise the latest literatures of biomaterial and stem cell composite for broad biomedical applications in tissue engineering and regenerative medicine. Collectively, we retrospect the current advancement of biomaterial engineering and science, and highlight the multifaceted biomaterial-assisted stem cell-based tissue engineering and regenerative medicine, and in particular, the biomaterial-based composites with mesenchymal stem/stromal cells (MSCs) and the derivatives (e.g., exosomes, small microvesicles) for intractable disease administration.

The Historical Overview of Stem Cells

Stem cells of hierarchical clustering have emerged as alternative and promising sources for tissue engineering and regenerative medicine. Owing to the unique self-renewal and multi-lineage differentiation attributes, stem cell-based cytotherapy has evoked great expectations in handling numerous refractory and recurrent diseases. Of note, quality control (QC), good manufacturing practice (GMP), and guidelines for stem cells and the derivations are prerequisites for evaluating the safety and efficacy of stem cell-based remedies. In this book, we principally focus on the definition, classification, signatures and functions, safety and efficacy of stem cells, together with the core concerns upon stem cell-based clinical applications and investigational new drug (IND) and new drug application (NDA). Collectively, this book will effectively benefit the novel stem cell-based tissue engineering and regenerative medicine.

Animal Models of Alzheimer's Disease

As the number of Alzheimer's Disease (AD) cases continues to climb throughout the third decade of this century, researchers have yet to find a cure for the debilitating disease, even though the condition was first diagnosed in the early 1900s. Since then, scientists have elucidated its etiology, which shows that AD pathogenesis is a unique, complex amalgam of genetic, aging, comorbidities, and environmental factors for each patient. In no small part, animal models of AD have been instrumental in revealing disease pathways correlated to cognitive dysfunction and behavioral deficits; moreover, they have been indispensable as preclinical models for potential drug candidates. Both small and large mammalian models of AD will be surveyed and discussed, ranging from mice and rats to dogs, cats, sheep, pigs, and primates. Each of the model's advantages and disadvantages will be closely examined.

Subject Index

References

Sex in the Brain and Spinal Cord

Predictive Analytics Algorithm for Early Prevention of Brain Tumor using Explainable Artificial Intelligence (XAI): A Systematic Review of the State-of- the-Art

Advancement in the medical field promotes the diagnosis of disease through automation methods and prediction of the brain tumor also plays an important role due to the fact that millions of people are affected by brain tumor and the rate of affected people is increasing every year randomly. Hence, in saving the lives of many individuals, the early detection of the disease plays an important role. Using the MRI Images, it’s easy to find the location and existence of the tumor. Expert manual diagnosis is playing a vital role in detecting the information about the tumor and its type. Though there are various models that can detect tumor location with the help of ML models in the medical field, somewhere there is a lag in the success of these models. Deep learning is one of the widely used approaches for the same. But the black-box nature of these machine-learning models has somewhat limited their clinical use. Explanations are essential for users to know, trust, and well manage these models. The chapter proposes dual-weighted deep CNN classifiers for early prediction of the presence of brain tumor along with the explanation-driven DL models such as Local Interpretable Model-agnostic Explanations (LIME) and SHapley Additive explanation (SHAP). The performance and accuracy of the planned model are assessed and relate with the existing models and it is expected that it will produce high sensitivity as well as specificity. It is also expected to perform well by means of precision and accuracy.

Neurological Examination

A neurological exam, also called a neuro exam, is an evaluation of a person's nervous system that can be done in the physcians. It may be done with instruments, such as lights and reflex hammers. It usually does not cause any pain to the patient. The nervous system consists of the brain, the spinal cord, and the nerves from these areas. There are many aspects of this exam, including an assessment of motor and sensory skills, balance and coordination, mental status (the patient's level of awareness and interaction with the environment), reflexes, and functioning of the nerves. The extent of the exam depends on many factors, including the initial problem that the patient is experiencing, the age of the patient, and the condition of the patient.

Analysis of Human Gait by Selecting Anthropometric Data Based on Machine Learning Regression Approach

This paper aims to elucidate a method to simulate human gait, which can help design a fully functional exoskeleton to rehabilitate the human lower limb. We present a method to calculate the forces and moments of each lower limb joint using human anthropometric parameters and free body diagrams. Various forces and moment of forces of lower limb joints have been calculated. The anthropometric data is evaluated using the linear regression approach. Also, in this work, we have simulated the normal human walking pattern. The forces and moments acting on lower limb joints are calculated in horizontal and vertical directions, and the human gait was simulated for a speed of 1.8m/s. The estimated results can be used as input parameters for the development of an exoskeleton for the rehabilitation of the human lower limb.

Harnessing the Neurological Properties of Indian Brain Health Booster Brahmi

Brahmi (Bacopa monnieri Linn.) is a well-known therapeutic herb used in a broad spectrum of conventional medicines to alleviate various ailments, prominently those involving intellect, anxiety and mental health. In Ayurveda, it is classified as Medhya rasayanas (meaning intellect rejuvenator) and claimed to be a cognitive nutrient and memory enhancer. Although the plant possesses a plethora of compounds, its neurological activity is mainly attributed to its major phytochemical constituents, i.e., bacoside saponins. Majorly isolated compounds are dammarane triterpenoids glycone and aglycones. There are several reports published with neurological activities on Bacopa monnieri to validate traditional claims through scientific findings. Some therapeutic formulations containing standardized extracts of Bacopa monnieri have also been developed for the betterment of mental health. Besides, being neuroprotective, the plant is reported to possess anti-inflammatory, analgesic, and antipyretic properties and systemic disorders like cardiovascular, hepatic, gastrointestinal, myocardial ischemia, respiratory problems, opioid-related nephrotoxicity and hepatotoxicity. The present chapter described the phytochemical profiling, extraction and isolation, neurological properties, as well as toxicological and clinical studies of the plant.

Basic Life Support

The chapter is essential for the dental chairside assistant. It details the first step that needs to be provided to the victim of a life-threatening injury, cardiopulmonary arrest, or sudden cessation of breathing. It deals with basic medical skills, and if implemented, these can enable saving a life. The basic life support provider needs practical training, which needs to be further updated at regular intervals. The details of various algorithms, chances of survival, sequence of action, airway obstruction in children, method of defibrillator use and cardiopulmonary resuscitation are also explained in detail.

Theranostics Micelles for Brain Tumor Diagnosis and Treatment

Brain cancer is considered one of the most vicious and devastating tumors owing to its poor prognosis and high mortality rate. Common strategies for treatment include surgery, radiation, and chemotherapy. Unfortunately, these are limited due to their invasive nature and the inherent difficulties of brain surgery, given there is a high possibility of tumor relapse. Further, radiation and chemotherapy have a non-selective harmful effect on normal tissues, accompanied by limited drug delivery due to the presence of various barriers, including the blood-brain barrier. For this reason, the theranostic approach was developed by incorporating one or more therapeutic and diagnostic agents in a single nanocarrier moiety which could be modulated at its surface with certain proteins, legend, surface markers, or a stimuli-responsive agent that is capable of selectively targeting the tumor site after passing through the blood-brain barrier. This new field will permit the early and precise detection of cancer tissue, facilitate the process of drug delivery and assist in monitoring treatment outcomes. Micelles are considered one of the most commonly used nanocarriers due to their high stability and loading capacity, along with efficient release controlling properties. This chapter will present brief information about brain anatomy and cancer, and will discuss the main strategies implemented in the diagnosis and treatment of brain cancers. Furthermore, it will introduce the theranostic micelle approach by highlighting micelles types and preparation techniques, as well as explain the different barriers and approaches to targeting.

Anatomy and Physiology of the Brain: Pathophysiology of Brain Tumor

The brain is an efficient processor of information. It is the most complex and sensitive organ in the body and is responsible for all functions of the body, including serving as the coordinating center for all sensations, mobility, emotions, and intellect. The magnitude of its myriad function is often realized usually when there is a disruption of the nervous system due to injury, disease, or inherited predispositions. Neuroscience is the field of study that endeavors to make sense of such diverse questions; at the same time, it points the way toward the effective treatment of dysfunctions. The two-way channel of information: findings from the laboratory leading towards stricter criteria for diagnosing brain disorders and more effective methods for treating them and in turn, the clinician's increasingly acute skills of diagnosis and observation that supply the research scientist with more precise data for study in the lab diligently expands the field of neuroscience. Tumors of the brain produce neurological manifestations through several mechanisms. Stronger hypotheses about the mechanism of a disease can point the way toward more effective treatments and new possibilities for a cure. In highly complex disorders of the brain, in which many factors genetic, environmental, epidemiological, even social and psychological—play a part, broadly based hypotheses are exceedingly useful. With the advancements in technology and a better understanding of brain anatomy and physiology, the quest to discover an efficient cure for life-threatening tumors of the brain is underway.

Nanocollagen-graphene-antibiotic for Wound Healing

Nanotechnology is a greatly advancing field of scientific research due to its largely untapped potential, which may apply to various clinical uses. This book chapter focuses on the potential use of nanocollagen, graphene, and antibiotic components in biomaterial fabrication for wound healing. Nanocollagen is simply regular collagen broken down to the nanometer scale. Its nanocollagen-based biomaterials also conform to the ideals of tissue engineering, which are excellent biocompatibility with a high bioabsorption rate and little to no antigenicity while having an extensively cross-linked structure suitable for cellular growth and metabolism. Nanocollagen can be fabricated through electrospinning, nanolithography, self-assembly, and others. The physiology of wound healing follows specific proceedings, which are haemostasis, inflammation, and remodelling stages. The wound healing process may be improved through the use of nanocollagen biomaterials, together with the addition of graphene and antibiotics. Nanocollagen biomaterials aid in acting as a barrier for the wound against infections while providing collagen in the nanoscale to accelerate healing. The addition of antibiotics into the nanocollagen biomaterial aids in preventing bacterial infection by the inhibition of biofilm formation. Graphene, specifically in its oxide form, also acts as an antibacterial agent while potentially providing mechanical durability to the biomaterial scaffold. Along with the benefits of graphene oxide application in wound healing, its challenges are discussed in this book chapter. With that, this book chapter suggests the beneficial combinatorial factors of nanocollagen, graphene, and antibiotics that can potentially produce biomaterials with strong antibacterial properties while accelerating wound healing.

Biological Significance of Steroids

Steroids display varied biological functions and play a crucial role in the fascinating fields of biology, chemistry, and medicine.Steroids encompass wideranging natural products which are abundantly encountered in eukaryotic organisms. These exhibit a pivotal role in regulating the cellular functions of animals, plants, and fungi. Furthermore, they act as chemical messengers in the human body and get secreted in the systemic circulation and extracellular fluids, where they regulate metabolic, immune, and reproductive functions. Steroids are the fundamental components of cell membranes and serve primarily as signalling molecules. This chapter gives a comprehensive overview of physiologically active steroids in various organisms.The biological activities of various steroid classes have been discussed in detail. Glucocorticoids are a class of steroid hormones that regulate the metabolic processes involving the formation of glucose from amino acids and fatty acid deposition of glycogen in the liver. Another important group of hormones, called mineralocorticoids, helps in balancing water and electrolyte content in the body and primarily affects the kidney. The principal class of steroids viz. the sex hormones are essentially crucial for the development and maintenance of reproductive function and cause stimulation of secondary sexual characteristics in humans. To summarize, steroids stabilize and regulate the structure and functions of cellular membranes and play a crucial role in regulating growth and development.

Biotransformation of Steroids: Accelerating Discovery of New Drugs in the Pharmaceutical Industry

Natural products account for 60% of the total market, making them a major source of drug discovery. Some of these are sourced from the cultivation of microorganisms. Microbial transformation is an example of the application of the cultivation of microorganisms. It is a method of modifying the chemical structure of compounds such as steroids by microorganisms. The diversity of the possible reaction types in microbial transformation includes the process of oxidation, hydroxylation, esterification, isomerization, reduction, acetylation, hydrogenation and glycosylation. Therefore, screening of new microbial strains for specific bioconversions is essential for bioprospecting. This chapter reviews a range of previous studies that have used fungi for biotransformation.

A Survey on Brain-Computer Interface and Related Applications

Brain Computer Interface (BCI) systems are able to communicate directly between the brain and computer using neural activity measurements without the involvement of muscle movements. For BCI systems to be widely used by people with severe disabilities, long-term studies of their real-world use are needed, along with effective and feasible dissemination models. In addition, the robustness of the BCI systems' performance should be improved, so they reach the same level of robustness as natural muscle-based health monitoring. In this chapter, we review the recent BCIrelated studies, followed by the most relevant applications. We also present the key issues and challenges which exist in regard to the BCI systems and also provide future directions.

Neuroprotective Activities of Cinnamic Acids and their Derivatives

Neurodegenerative disorders are considered major global health problems associated with nervous system dysfunction, progressive neuronal cell loss with aging, and several pathological and sporadic factors. Parkinson’s disease, Alzheimer’s disease, Prion disease, Huntington’s disease, and multiple sclerosis are the main neurodegenerative diseases that raise significant concern among health scientists. The etiology of different neurodegenerative diseases is different, and they majorly affect the nervous system, including the brain, spinal cord, and peripheral nervous system. Neurodegenerative diseases are linked with motor dysfunction, anxiety, memory loss, depression, cognitive impairments, etc. These diseases can be hereditary or caused by toxicity, metabolic disorders, or pathological changes in the brain. Therefore, interest has been growing in the development of different neuroprotective agents of natural origin that could work effectively against these diseases. In that aspect, phytochemicals have shown high potential with minimal side effects in various in vitro and in vivo studies. Cinnamic acids with phenylpropenoic moiety are abundant in many natural resources. These are available in many forms, such as ferulic acid, caffeic acid, etc. They also have a variety of pharmacological properties, including anti-inflammatory, anti-oxidant, anti-amyloid, and neuroprotective properties. This chapter summarizes the role of naturally occurring cinnamic acids and their derivatives to develop the mechanistic aspects of neuroprotective therapeutics in neurodegenerative diseases. Future challenges are also discussed to provide beneficial information and therapeutic strategies.

Multi-functional Ligands and Molecular Hybridization: Conceptual Aspects and Application in the Innovative Design of Drug Candidate Prototypes for Neurodegenerative Diseases

The rapid increase in the incidence of dementia has enormous socioeconomic impacts and costs for governmental health systems all over the world. Despite this, finding an effective treatment for the different types of neurodegenerative diseases (NDs) so far represents a challenge for science. The biggest obstacles related to NDs are their multifactorial complexity and the lack of knowledge of the different pathophysiological pathways involved in the development of each disorder. The latest advances in science, especially those related to the systems biology concepts, have given new insights for a better comprehension of such multifactorial networks related to the onset and progression of NDs, and how Medicinal Chemists could act in the search for novel disease-modifying drug candidates capable of addressing the multiple pathological factors involved in neurodegeneration. The multi-target directed ligands (MTDLs) concept has captivated and opened new windows for the creativity and rationality of researchers worldwide in seeking innovative drug candidates capable of modulating different molecular targets by a single multifunctional molecule. In fact, in the last two decades, thousands of research groups have dedicated their efforts to the use of molecular hybridization as the main tool for the rational design of novel molecular scaffolds capable of expressing multi-target biological activity. In this way, this chapter addresses the most recent pathophysiological hallmarks of the most highimpact NDs, represented by Alzheimer’s, Parkinson’s, Huntington’s diseases, and amyotrophic lateral sclerosis, as well as the state-of-art in the design of new MTDLs, inspired mostly by natural products with improved druggability properties.

Assistive Technology for Home Comfort and Care

Every second, individuals with physical and cognitive disabilities struggle so much to do some actions that normal people easily do within seconds. Assistive Technologies (AT) are those modules or sets of arrangements that aim to make life easy for disabled people, by stopping blockage and improving their mental and physical power. They improve their working capability, confidence, standard of living, and optimism. In modern times, Artificial Intelligence (AI) and technologies are developing rapidly, and new machines, motors, and mostly electronic devices powered by powerful batteries are being built every second. These are making it possible for disabled people to become self-dependent. Today, Assistive technology devices are efficient and suitable for disabled people. This chapter aims to provide in-depth knowledge about various types of disabilities, how disabled people face different problems and challenges, and how they can select and use assistive devices and mobile apps to live independently and comfortably.

Overview, Category and Ontology of Assistive Devices

The majority of physically challenged and elderly people demand a lot of care when it comes to assistive technologies that can provide tailored services to their needs. The primary concern of advancement in Assistive technology is to address a wide variety of disabilities and intellectual impairments for societal benefits by reducing welfare costs and allowing for an efficient workforce. To better respond to changes brought on by modernity, it is necessary to understand how assistive technology interacts in that group. The broad range of assistive devices in the continuum of assistive technology can help people with various impairments. Based on the underlying technology, the Categorization of assistive devices has important implications for clinical usage when examined through the perspective of social phenomenon. In the realm of Assistive Technology, a consistent focus on the relationship between the individual and the supported activity within certain contexts is essential. Assistive technology can be viewed from the perspective of various performance areas. The Ontology-based Assistive Devices that are among the finest within common, everyday contexts for more relevant applications are interesting. This chapter explores all those essential elementary and general considerations of assistive devices that form the bases of Assistive technology and brings out the categories of assistive devices and the various application domains where assistive devices can be served as a derivative of a particular ontology. The chapter focuses on the various performance areas by addressing the issues associated with Assistive technology Practice.

Subject Index

Tinospora cordifolia in Neurodegeneration: A Strong Antioxidant and Anti-inflammatory Phytotherapeutic Drug Candidate

Tinospora cordifolia is a Rasayana herb of Ayurveda, commonly known as “Heavenly Elixir” or “Amrita”, and one of the most exploited herbs in herbal medicines. T. cordifolia is well reported for its various pharmacological properties, such as anti-diabetic, anti-inflammatory, antipyretic, immunomodulatory, anti-cancer, cardioprotective, neuroprotective, and hepatoprotective activities. The prevalence of neurodegenerative diseases and other neurologic disorders is increasing worldwide. Oxidative stress and neuroinflammation are among the major pathologic mechanisms underlying neurodegenerative diseases. This chapter discusses the pieces of scientific evidence of the beneficial effects of T. cordifolia in various brain-related ailments. Various research groups have demonstrated the ability of T. cordifolia and its extracts to normalize oxidative stress and suppress the inflammatory response against various causative agents, and thus suggested that T. cordifolia has the potential to be a neurotherapeutic drug candidate in the future.

Modulations of SIRTUINs and Management of Brain Disorders

Neurodegenerative disorders are the conditions in which neurons of the central and peripheral nervous systems degenerate. Various cellular and molecular processes are associated with the progression of such degeneration, including inflammation, apoptosis, and axonal degeneration. Recently, SIRTUINs have emerged as one of the key factors associated with neurodegenerative disorders. SIRTUINs are involved in the regulation of several cellular and molecular processes in neurons of the nervous system through the deacetylation of target proteins. The chapter focuses on the modulatory role of SIRTUINs in neurodegenerative disorders and their potential therapeutic application.

Delineating the Neuroinflammatory Crosstalk in Neurodegeneration and Probing the Near Future Therapeutics

Neurodegenerative disorders are threatening mankind with significant health and economic burden. Neurodegeneration involves the deterioration of neurons in the central nervous system (CNS), resulting in decreased neuronal survival. Therefore, it is of utmost requirement to develop a promising pharmacological strategy to minimize or prevent the progression of the underlying disease pathogenesis. In neurodegenerative disease conditions, neurons and glial cells present in the specific brain regions are damaged and depraved, resulting in specified disease symptoms in the patients. Neuroinflammation plays a major role in the degeneration of neuronal cells by regulating the expression of interleukin-1 beta (IL-1β), IL-6, IL-8, IL-33, tumor necrosis factor-alpha (TNF-α), chemokines Cxcl3 (C-C motif) ligand 2 (CCL2), CXCL5, granulocyte-macrophage colony-stimulating factor (GM-CSF), glia maturation factor (GMF), substance P, reactive oxygen species (ROS), reactive nitrogen species (RNS), impaired tuning of immune cells and nuclear factor kappa-B (NF-κB). Considering this, it is very important to understand the in-depth role of neuroinflammation in the initiation and progression of various neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), as well as Multiple Sclerosis (MS). Recent shreds of evidence have suggested that using exogenous ligands to approach various biological molecules or cellular functioning that modulates the neuroinflammation, such as microglia response, P2X7 receptors, TLR receptors, oxidative stress, PPARγ, NF-κB signaling pathway, NLRP3 inflammasome, caspase-1 signaling pathway, and mitochondrial dysfunction, helps to combat neurodegeneration in a variety of diseases. Thus, targeting the neuroinflammatory drive could provide a beacon for the management of neurodegenerative diseases. Here, we have attempted to provide comprehensive literature suggesting the role of neuroinflammation in neurodegeneration and its implication in the development of near-future neurotherapeutics.

Natural Products: Antibacterial, Anti-fungal, and Anti-viral Agents

The existence of substantial evidence about the development of resistance to a drug among microbes has gained a lot of attention from the scientific world. To address this problem, researchers have been conducting experiments and testing strategies, including screening various molecules and using plant-derived natural products to ascertain if these substances can serve as an untapped source of antibacterial, anti-viral, and anti-fungal agents. The non-toxic, non-synthetic, causing minimal side effects, and cost-effective nature of these substances make the development of new anti-microbials heavily dependent on the use of many of these existing products and increase the demand for finding new natural products that are yet to be discovered. These plant-based natural products offer great promises to provide the best protection against infections and pathogenesis in many diseases. Furthermore, the biodegradable nature of many of these products increases their chances of being chosen by farmers and plant biologists to use to combat microbial pathogenesis. This chapter covers the current insights on the conflicts and opportunities of popular plant-derived natural anti-microbial compounds containing a reservoir of secondary metabolites, viz.. flavonoids, alkaloids, terpenes, coumarins, phenols and polyphenols. The chapter lists natural vegetable products, which serve as potent anti-bacterial and anti-fungal agents, and describes various plant extracts, which exhibit bacterial quorum sensing, biofilm as well as efflux pump inhibitory activity. Previous studies have demonstrated the effectiveness of these plant-based natural products in the treatment of neurodegenerative diseases as well. This chapter also summarizes the neuroprotective activity of these products and their potential to serve as therapeutic agents to block or delay the progression of disorders.

Sleep Medicine in Iran: Current Practice, Challenges, and Future Direction

The Iranian Sleep Medicine (ISM) Society, established in 2005, has worked to increase public knowledge of how important sleep is to maintain health in the community and safety on the roads. The ISM has also had a strong role in the implementation of sleep tests and laboratory standards in collaboration with the Ministry of Health, training sleep specialists to diagnose and treat sleep disorders, certifying sleep labs to ISM standards, and conducting much needed research to improve sleep amongst Iranians. In this chapter, we will first introduce the current healthcare system highlighting the practice of sleep medicine in Iran. Next, we identify three challenges in delivering sleep medicine to millions of Iranians with potential solutions. The challenges are: (1) a limited number of trained sleep medicine specialists unequally distributed across all districts; (2) a limited number of certified sleep labs; (3) the need for insurance to pay for the diagnosis and treatment of sleep disorders such as obstructive sleep apnea, narcolepsy, and insomnia. Lastly, we present future directions for Iranian sleep research including much needed population-based studies to assess the prevalence of sleep disorders. While much progress has been made since 2005 to improve sleep health in Iran, we still have much work to do to reach our goal of significantly reducing disparities and promoting sleep medicine all over Iran toward a healthier future.

Polymer Nanocomposite Technologies Designed for Biomedical Applications

The combination of polymer composite technology and nanotechnology leads to the design of polymer nanocomposites. They represent a novel alternative class of materials to traditional composites with versatile properties which are suitable for biomedical applications. The addition of nanofillers to polymer composites enhances their mechanical and biological characteristics. The enhancement in various properties depends on the polymer matrix, filler, and matrix-filler interaction. The major issue faced in biomedical research during product development is the lack of biocompatibility and biodegradability. The primary factor that has to be considered for composite development is the proper choice of materials. There is a growing demand for the design of personalized medicine with the outbreak of many chronic ailments and genetic disorders. The properties of polymer nanocomposites can be customized for various biomedical applications. The characteristic features of supramolecular nanocomposites which act as smart materials with tuned properties can be exploited for tissue engineering, responsive drug and hormone delivery, regenerative medicine, bioimaging, ocular, dental and orthopedic applications. Many hybrid biopolymer composites which exhibit promising biomedical applications are developed by researchers. Their properties can be tailored for making biomedical devices also. This chapter highlights a brief but focused overview of biomedical applications of bio-based polymer nanocomposites, carbon-based polymer nanocomposites, metal-organic framework/polymer nanocomposites, shape memory polymer nanocomposites, hydrogels, self-healing polymer nanocomposites and stimuli responsive polymer nanocomposites.

A Game-Based Neurorehabilitation Technology to Augment Motor Activity of Hemiparesis Patients

Stroke recovery is the subsequent goal of stroke medicine. Rehabilitation and recovery research is exponentially increasing. However, several impediments impede the progress in the design of neurorehabilitation technology for stroke patient recovery. The conventional rehabilitation techniques for stroke recovery have some limitations like the absence of standardized terminology, poorly described methods, lack of consistent time frames and recovery biomarkers, reduced participation, and inappropriate measures to examine outcomes. Stroke recovery is challenging for many survivors. They require highly functioning and quick treatment accompanied by a gradual acceptance of brain improvement and human behavior. Therefore, there is an immediate need for neurorehabilitation technology to improve the quality of activities of daily life (ADLs) of those disabled. The method adopted is the design of neurorehabilitation technology using game-based systems that enhances the motor activities of hemiparesis patients.

Polymeric Nanoparticles as Drug Delivery System: Basic Concepts and Applications

Delivering drugs through various delivery systems into the body for successful treatment of diseases is most entrancing deeds for the pharmaceutical analyst. Conventional drug delivery systems have various hindrances like loss of medication and poor bioavailability of drugs. Polymer-based nanocarriers such as polymeric nanoparticles upgrade bioavailability of drug, delivery of drug to specific site and improve solubility of drugs. They are widely explored as controlled, precise, sustained and continuous release systems for drug delivery and are easily incorporated and appropriate for practically all parts of nanomedicines and bring new trust in field of drug conveyance by redesigning drug viability and diminishing drug toxicity. This chapter mainly focuses on polymers and techniques engaged with advancement of polymer-based nanoparticles and their applications in therapeutic intervention.

Postoperative Management of Postnatal Complications

The postpartum period is the time after delivery when physiological changes by the pregnancy return to the previous state. Primary postpartum haemorrhage takes place during the first 24 hours, and secondary postpartum haemorrhage occurs between 24 hours and 6 weeks after delivery. Many disorders can occur in the immediate postpartum period, there is a considerable source of morbidity and mortality in women of reproductive age, which can be mild to severe and life-threatening. Protocols aimed at the multidisciplinary management of postpartum haemorrhage, and together with the use of coadjuvant hemostatic agents, the activation of massive transfusion protocols in a responsible manner, and surgical management have improved the prognosis of these patients.

Anesthetic Management of the Pregnant Patient with Comorbidities

An increase in pregnant patients with comorbidities has been seen in the last decade. Nevertheless, these patients are able to enjoy longer and better quality lives nowadays. During pregnancy, patients can experience decompensations of their chronic disease which can be sometimes challenging for the medical team. Complexity has risen; that is why the anesthesiologist must be updated and capable of facing different scenarios both in the delivery room and before or after birth. This chapter offers a practical and synthetical approach to the most common situations in which a general anesthesiologist can be involved, aiming to emphasize main points for safe and accurate anesthetic care.

Locoregional Anesthesia Comments in the Obstetric Patient and Eventual Complications

Labor pain is associated with increased stress response and when it is excessive, it may lead to hypoxemia and fetal acidosis. The most important factor in obstetric analgesia is the desire for pain relief by the patient and neuraxial analgesia is the mainstay procedure in labor and in anesthesia for cesarean delivery. Continuous lumbar epidural analgesia is the mainstay of neuraxial labor analgesia. There are other methods, such as intrathecal block or combined spinal-epidural, that can be useful in specific cases. Despite being the safest and most effective method, the epidural labor analgesia may have some complications. Other therapies include bilateral paracervical block and pudendal block, which provide rapid onset analgesia (2–5 min). Although useful, they require training and are risky in cases of placental insufficiency or prematurity.

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Modulation of Proinflammatory Cytokines by Flavonoids in the Main Age-related Neurodegenerative Diseases

Aging is a process associated with distinctive changes in physiological functions and physical appearance that result from progressive tissue degeneration, harming the structure and function of vital organs. Illnesses that are particularly frequent in people 65 years of age and older are generally grouped as age-related diseases or aging-related diseases and include neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), which are caused by progressive degeneration and/or neuronal death to produce debilitating conditions, and they have no cure. For these illnesses, the most important risk factor is aging. Aging involves changes in neuroendocrine and inflammatory responses and presents a stage with chronic and low-grade inflammation, characterized by a general increase in the production of proinflammatory cytokines, inflammatory markers, and cellular senescence. Herbal medicine, as well as various components of the human diet, including vegetables, cereals, and fruits, contain widely varied phytochemicals including flavonoids, which are the most common polyphenolic compounds. Epidemiological studies suggest that a higher intake of flavonoid-rich foods and beverages is associated with better cognitive outcomes, lower dementia rates, and reduced risk of neurodegenerative diseases. Moreover, numerous preclinical studies have shown that these compounds have a therapeutic effect on animal models of human degenerative diseases and highlight the anti-inflammatory effect of flavonoids by decreasing the activated glial cells and several proinflammatory mediators. Much modern scientific research has focused on establishing biological activities of purified single compounds to provide an evidence base for the rationale of traditional practice, and also to integrate these into modern medical practice.

Role of Withania somnifera (Ashwagandha) in Neuronal Health

Neurodegenerative disease refers to the progressive deterioration of neurologic function which leads to loss of speech, vision, hearing, and movement. It is also associated with seizures, eating difficulties, and memory impairment. Natural products have emerged as potential neuroprotective agents for the treatment of neurodegenerative diseases due to the enormous adverse effects associated with pharmacological drugs. Withania somnifera (Ashwagandha) is a traditional Ayurvedic medicine, used in India as a general tonic. It contains withanolides, and phytochemicals that may have adaptogenic properties. Studies show that W. somnifera is a neuroprotective agent and can protect the brain from oxidative stress and inflammation. This explains its ability to protect from mood disorders. In this review, we have reviewed the available evidence of W. somnifera and its phytochemicals for neurodegenerative disorders.

Polyphenols and Flavonoids: Chemical, Pharmacological and Therapeutic Aspects

Polyphenols and flavonoids represent a group of compounds characterized by a large assortment of phenolic structures, which can be naturally found in vegetables, roots, stems, flowers, grains, and fruits. Thanks to their biological activities, molecules belonging to these classes of compounds, besides their nutritional role, have found applications in several fields such as pharmaceutical, cosmetic, and nutraceutical. In fact, like many natural derivatives from plants, they possess several therapeutic properties, including antitumor, anti-oxidative, anti-neurodegenerative, antimicrobial and anti-inflammatory effects. Nowadays, the growing interest in polyphenolics and flavonoids translates into constant research to better define their pharmacological mechanism of action. Extraction studies in order to obtain pure compounds with a more defined biological activity, as well as pharmacokinetic studies to understand the bioavailability, the involved metabolic pathways and the related active metabolites, are carried out. Molecular docking studies are also continuously in progress to expand the field of application. Moreover, toxicity experiments to clarify their safety and studies about the interaction with other compounds to understand their selectivity of action are continuously forwarded and deepened. Consequently, many recent studies are aimed at introducing polyphenols, more specifically flavonoids, and their semi-synthetic derivatives, in the prevention, management and treatment of several diseases.

Craniofacial Growth and Development in Children

Human growth, development, and maturation are multifaceted processes that involve different aspects, including biological, physical, social, and intellectual aspects. Between conception and maturity, the size and complexity of the human body change dramatically. A multitude of changes in sensory, cognitive, and motor coordination are also associated with the development of an individual from infancy to adolescence and are related to brain growth and maturation. All the different facets of development are, however, interrelated. This chapter summarizes the various concepts, principles, theories, factors affecting growth and the parameters used to measure and assess maturity from time to time.

Biomaterials in Gene Therapy for Soft and Hard Tissues

Bone healing and formation are under the control of growth factors. Among these factors, bone morphogenetic proteins (BMPs) have a vital role in bone and cartilage maintenance and formation. BMP itself belongs to the superfamily of transforming growth factor β (TGFβ). Although, the use of recombinant BMPs has no significant association with the treatment of bone fractures, arthroplasty, pseudoarthrosis or other bone-related diseases. Recent advancements in genetic engineering have led to the foundation of gene therapy. Gene therapy uses genes to be incorporated in the living cells to replace defective genes or manipulate gene expression for therapeutic purposes. Gene therapy is emerging for the treatment of diseases with approval in Europe where it is in the marketing surveillance phase (Phase IV Clinical trial). This technique has also been tested for the incorporation of osteogenic genes in stem cells for repairing spinal fusion and recovering defects in bones in preclinical models. Therefore, gene therapy has the potential for the treatment of different diseases and has the advantage over the use of recombinant proteins. In this chapter, we have discussed gene therapy, its mechanism, delivery system and its use in tissue engineering (soft and bone tissue) for clinical application.

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Cervical Endoscopic Unilateral Laminotomy for Bilateral Decompression (CE-ULBD) – A Technical Perspective

Cervical endoscopic unilateral laminotomy for bilateral decompression (CEULBD) is an applicable surgical method in cases of central canal stenosis, usually associated with myelopathy. Other authors have shown the feasibility, safety, and efficacy of this method. They could also demonstrate more favorable perioperative benchmark data of this procedure than anterior cervical discectomy and fusion (ACDF) in terms of duration of surgery, blood loss, and hospital stay. In this chapter, the authors focus on the technological advances making this surgery possible. Moreover, the authors review the relevant surgical anatomy to enable the aspiring endoscopic spine surgeon to safely and successfully perform the CE-ULBD procedure. Experience in advanced endoscopic surgery in other areas of the spine is recommended before imparting on the posterior endoscopic decompression of the stenotic central cervical spinal canal. The authors have implemented CE-ULBD in formalized and wellstructured Endoscopic Spine Academy (Espinea®) training programs, intending to provide high educational standards to achieve favorable outcomes with the CE-ULBD procedure reproducibly.

Treatment of Thoracic Meningioma with Spinal Canal Decompression under Spinal Endoscopy

Extramedullary benign tumors of the spine may cause spinal cord compression. Patients may present with motor weakness and sensory loss in the extremities causing gait abnormalities. Surgical treatment is indicated when symptoms are no longer manageable. In this chapter, the authors present an 87-year-old female's case as an illustrative example of how the spinal endoscopy platform can be safely and effectively deployed in the treatment of such lesions. The example patient suffered from spinal cord compression from a large meningioma at the T7 level. The tumor was successfully removed via an endoscopic working cannula. The patient's symptoms improved, and a nine-month follow-up MRI scan showed adequate and maintained spinal cord decompression. This case example demonstrates that spinal endoscopy may be applied to an increasing number of surgical indications beyond the scope of degenerative disease. Further clinical investigation will need to show this technology's limits when treating benign tumors of the spine.

Endoscopic Intravertebral Canal Decompression after Spinal Fracture

Spinal endoscopy allows creating access to areas of the spine that are ordinarily difficult to reach, thereby reducing the collateral damage from extensive exposure to treat common degenerative or traumatic conditions of the spine. In this chapter, the authors present a case of endoscopic spinal canal decompression in a patient who sustained a burst fracture near the thoracolumbar junction. The endoscopic decompression technique was employed, which resulted in removing bone fragments, causing compression of the neural elements. The burst fracture was then stabilized with a percutaneous short pedicle screw construct. The patient did well with the hybridized endoscopic and minimally invasive decompression and stabilization technique. The authors are making a case for considering the endoscopic spinal surgery platform other than the traditionally accepted indications in the interest to diminish further blood loss, pain, and complication rates associated with spinal fracture surgeries.

Regenerative Medicine and Interventional Endoscopic Pain Surgery for Degenerative Conditions of the Spine

Regenerative medicine is a subspecialty of medicine that seeks to recruit and enhance the body's own inherent healing armamentarium in the treatment of patient pathology. In regenerative spine care, the intention is to assist in the repair and potentially replace or restore damaged tissue through autologous or allogenic biologics. In the authors' opinion, future spine care will likely evolve into a blend of prevailing strategies from interventional pain management and minimally invasive spine surgery. This form of spine care nowadays is commonly called interventional pain surgery. The interest in regenerative medicine in general and in interventional pain surgery of the spine is growing given the high patient awareness of problems with traditional spine surgery, whose focus is on decompression of pinched nerves and correction of spinal instability and deformity. However, reoperation- and complication rates are high with those open corrective spine surgeries as many of the spine's degenerative conditions are being only treated surgically when the disease has progressed to its end-stage. The sole application of image-based medical necessity criteria for surgical intervention in the spine seems slightly out of step with the growing demand for less aggressive and burdensome procedures that could perhaps be instituted earlier in the disease process where the goal is to heal the spinal injury or repair damage from the degenerative process more naturally. In this chapter, the authors review and discuss the current state of the art in regenerative biologic therapies and interventional pain care of the spine from their perspective as endoscopic spine surgeons. Simplifying therapeutic measures and strategies are at the heart of what patients request of us as surgeons. This field's applications in modern spine care are clearly in their infancy, except for fusion. The authors will discuss potential applications of select advanced biologics technologies and their attempts at integrating them into their endoscopic spinal stenosis surgery program to treat degenerative spinal disease and instability-related symptomatic end-stage degenerative vacuum disc disease in the elderly.

Artificial Intelligence Algorithms in the Identification and Demonstrating of Pain Generators Treated with Endoscopic Spine Surgery

Identifying pain generators in multilevel lumbar degenerative disc disease focuses on artificial intelligence (AI) applications in endoscopic spine care to assure adequate symptom relief with the targeted endoscopic spinal decompression surgery. Artificial intelligence (AI) applications of deep learning neural networks to analyze routine lumbar MRI scans could improve clinical outcomes. One way to accomplish this is to apply AI management of patient records using a highly automated workflow, highlighting degenerative and acute abnormalities using unique three-dimensional patient anatomy models. These models help with the identification of the most suitable endoscopic treatment protocol. Radiology AI bots could help primary care doctors, specialists including surgeons and radiologists to read the patient's MRI scans and more accurately and transcribe radiology reports. In this chapter, the authors introduce the concept of AI applications in endoscopic spine care and present some initial feasibility data validating its use based on intraoperatively visualized pathology. This research's ultimate objective is to assist in the development of AI algorithms predictive of the most successful and cost-effective outcomes with lumbar spinal endoscopy by using the radiologist's MRI grading and the grading of an AI deep learning neural network (Multus Radbot™) as independent prognosticators.

How to Generate the Superiority Evidence for Endoscopic Surgery for Common Lumbar Degenerative Conditions

Endoscopic spinal surgery affords the patient simplified and less burdensome spine care. Its superiority over open decompression surgeries has been long debated, and the current evidence is incomplete. The innovators and proponents of this procedure carry the burden of proof. The targeted endoscopic treatment of common spinal pain generators produces higher perioperative patient satisfaction than traditional spine surgery. This chapter discusses conventional spine surgery research's pros and cons of employing patient-reported outcome measures (PROM). They offer an alternative approach to establishing a better value proposition with the endoscopic versus open spinal surgery - the concept of durability analysis.

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Insights into the Recent Application of Rosmarinic Acid in Therapy

Herbs are key players in many traditional health care systems that have been used in medical practices since ancient times. The beneficial therapeutic effects of these medicinal plants resulted from the combinations of their secondary metabolite. Nowadays, the use of natural compounds is increasing around the world due to their relatively mild potentials and low side effects, Polyphenols are the most important compounds that exhibit diverse activities. Among these polyphenols, rosmarinic acid (RA) attracted much attention from the researchers since it was isolated as the main compound in many plants, like those of the Boraginaceae and Lamiaceae families such as Rosmarinus officinalis (rosemary) and Ocimum baslicum (sweet basil). It is an ester of caffeic acid and 3,4-dihydroxy phenyl lactic acid, which has a wide spectrum of biological, pharmacological and medicinal properties that can be useful in many pathological conditions. Moreover, it presents anti-inflammatory effects, which are attributed to the inhibition of lipoxygenase and cyclooxygenases and interference with the complement cascade. Furthermore, RA has been shown to prevent cell damage caused by free radicals, thereby reducing the risk of cancer. On the other hand, it also exerts powerful hypolipidemic, antioxidant, anti-atherosclerotic, anticancer and even hepato-protective activities. The current chapter aims to highlight the therapeutic potential of RA against a wide range of diseases. Given the current evidence, rosmarinic acid can be used as part of the daily intake in the treatment of several diseases, with predefined doses preventing cytotoxicity.

Engineered Nanomaterials as Emerging Water Pollutants

Nanotechnology has many advantages, and its applications are spread to every field, from engineering to medicine and space to agriculture. Owing to the immense advantages of nano-size particles, nano-based materials are widely applied in wastewater treatment. These nanomaterials are developed and utilized in different sizes, shapes, and chemical compositions. These nanomaterials are characterized by their unique physical, chemical and biological properties. Besides the immense benefits of nanomaterials, they also have few environmental implications. This chapter presents the pros and cons of nanomaterials and their implications on the environment. Further, the effect of various nanomaterials on the aquatic environment, including the behaviour and toxicity on the aquatic ecosystem, is discussed. Finally, future directions to minimize the toxic effect of nanomaterials on the aquatic ecosystem and the need for improvement in the nanomaterials are presented.

A Pathophysiological Approach To Current Biomarkers

Biomarkers are necessary for screening and diagnosing numerous diseases, predicting the prognosis of patients, and following-up treatment and the course of the patient. Everyday new biomarkers are being used in clinics for these purposes. This section will discuss the physiological roles of the various current biomarkers in a healthy person and the pathophysiological mechanisms underlying the release of these biomarkers. This chapter aims to gain a new perspective for evaluating and interpreting the most current biomarkers.

COVID-19 and Pregnancy

The SARS-CoV-2 pandemic has emerged as an unprecedented challenge to the current medical practice, including obstetrics. Being an acute situation, there is limited experience of the impact of COVID-19 in pregnancy. Various management protocols are being evaluated and modified frequently to address key concerns of maternal and neonatal health. Pregnancy is a unique bundle of two lives, and the physiological adaptation to the dual life adds to the uniqueness. The effect of COVID- 19 and its treatment on pregnancy (mother and fetus) and vice-versa, is a common quest for all pathologies. The other concerns are vertical and horizontal transmission in antepartum, intrapartum, and postpartum periods, respectively. The immunosuppression as a part of physiological changes during pregnancy apparently raises apprehension of higher risk of viral infection or probability of severity of infection during pregnancy. The same has also been observed with previous virus infections in history like severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), etc., although available literature suggests that the risk of developing COVID-19 for pregnant women is not similar to the non-pregnant adult population. The small risk of developing a serious condition during pregnancy is inevitable, and the contagiousness of the virus is a major concern for the neonate and attending family. Some overlapping features of complicated pregnancy with severe COVID-19 require attention. Social distancing, anxiety, and psychological stress need to be kept in mind. There is an impact of financial stress on family; domestic violence can also not be undermined during this crisis period. Access to health facilities may also be affected in developing countries due to the lockdowns, quarantine of pregnant women, caretakers, or health care workers (HCW), etc. The aerosol production during the intrapartum phase is challenging for both vaginal and abdominal routes of delivery, but the management of sudden catastrophic, life-threatening conditions associated with pregnancy can be a real threat for the team of health care workers. It is still early to comment on the long-term effects of the viral infection on the foetus, especially the exposure during the rapid embryogenesis period.

Subject Index

The “Stomachache” of Medicine: Concepts and Mechanisms of Abdominal Pain

Abdominal pain (AP) is by far among the most common complaints in healthcare institutions. Approximately every tenth patient in the acute setting is estimated to present with AP. Although cultural, geographical and sociodemographic variations exist, it is an outstanding complaint in all patient groups, independent of age and gender. Although it can be a manifestation of an intraabdominal pathology itself, a serious systemic or extraabdominal condition can be revealed following a thorough investigation of AP. Therefore, it is vital to evaluate the patient systemically, a focused but elaborate history, and extensive physical examination not confined to the abdomen in order to establish important diagnoses. Inspection, auscultation, percussion, superficial and deep palpation are important elements of the examination methods for the abdomen. Each positive or negative finding on examination should be interpreted cautiously for the individual patient. After history and evaluation narrow the list of differential diagnoses (DD), ancillary investigations including laboratory tests and radiological modalities can be ordered.

Rheumatoid Arthritis: Introduction

Rheumatoid Arthritis elaborated as Rheumatoid Arthritis is a systemic chronic inflammatory condition that might affect numerous organs and tissues in a human body, but mainly it attacks the synovial joints. These methods result in the inflammatory synovitis (synovium) response. Factors that lead to an increase in the risk of rheumatoid arthritis are age, sex, family history, smoking, obesity, and exposure to pollutants. RA holds the ability to put a person at a higher risk of developing other medical conditions if it is not controlled timely. A syndrome named carpal tunnel is another common condition found in people suffering from rheumatoid arthritis. Trauma, infection, smoking cigarettes are some of the examples of external triggers which can trigger the reaction of the auto-immune system, which results in chronic joint inflammation and synovial hypertrophy in addition to a potential of other manifestations, which will be theorized for going on in people prone genetically. The pathological process of the disease usually results in destructing the articular cartilage as well as the joints ankylosis. Rheumatoid Arthritis could also result in diffusive lung inflammation, sclera, pleura, pericardium, as well as nodular lesions, which are also common in subcutaneous tissue. However, the causes of RA are still not known, the autoimmunity holds an important part in both the progression and chronicity. Rheumatoid Arthritis is a systemic disorder. RA can be prevented by using coldwater, living fish oil, from the herring, cod, mackerel, and salmon fish, which contains omega-3 fatty acids in high amounts, Vitamin-D supplements, and adopting the lifestyle modifications such as avoiding smokingand weight loss.

Reproductive Cloning

Hearing the name “Dolly” was and still stirs the minds of professionals and non-specialists towards the term “cloning”, but the way of producing dolly is not the only aspect of cloning. Cloning is defined as the techniques through which identical or virtually identical individuals can be produced. Based on this definition, in this chapter, we are trying to clarify the different applications, aspects, and techniques of cloning such as gene cloning, therapeutic cloning, but to focus on reproductive cloning. Reproductive cloning is the method of making a genetically similar clone of a whole organism. Then it is needed to be discussed with all the scientific thoughts around it, advantages, disadvantages, legal or illegal, and comparing it to other aspects and this is our aim in this chapter.

Emerging Therapeutic Approaches for Neurodegenerative Diseases

The most common neurodegenerative diseases (ND) include Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), as well as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Protein misfolding and aggregation are the key hallmarks of these neurodegenerative diseases, which may lead to cell death, axonal regeneration failure, demyelination, and overall neuronal structural and functional deficits. Usually, ND is diagnosed at a very advanced stage and conventional therapies are directed at treating neurological symptoms but have no effect on disease progression. In general, several pathological processes contributes to misfolding proteins/protein aggregates and their postconsequences, including impairment of autophagy, microtubule destabilization, neuroinflammation, proteostasis, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress, calcium homeostasis, and neurogenesis impairment. Indeed, several signaling pathways critically linked with these pathological processes are now becoming attractive targets and investigated for their beneficial effects by restricting the progression of ND. In particular, certain signaling mechanisms and proteins found to show an integral involvement in the pathogenesis of ND and had shown promising results in preclinical and/or clinical contexts. For ex; novel autophagy stimulators, drugs acting on mTOR, NRF2, TLR, purinergic signaling; drugs acting on neuroinflammatory signaling pathways, Heat Shock Proteins (HSP), sestrins, sirtuins, some PDE-inhibitors, miRNA’s have gained a lot of attention in the therapy of ND and are included in the following discussion.

Multiple Sclerosis: Molecular Biology, Pathophysiology and Biomarkers

In the brain, multiple sclerosis is a chronic disease caused by immunemediated neurodegeneration. About 2.5 million people around the world suffer from multiple sclerosis (MS), and women are more prone to it. Neither clinical nor imaging biomarkers are used to diagnose or characterize the disease. Molecular biomarkers have been developed from immunology and neurobiology because they are well matched with causal path mechanisms and other disease characteristics, thus, limiting the number of molecular biomarkers used in clinical practice. Currently, the chapter discusses the attribute of flawless MS biomarkers and the challenges associated with developing newer biomarkers. The study also discusses the discovery of biomarkers from the blood and cerebrospinal fluid (CSF) that are useful for diagnosing MS, predicting its prognosis, and evaluating its therapeutic response and side effects.

Parkinson Disease: Molecular Biology, Pathophysiology and Biomarkers

Parkinson disease is a progressive neurodegenerative disorder that affects motor control of the body. The disorder is associated with the loss of neurons due to formation of protein aggregates that leads to the development of apoptosis and degeneration of the neurons. The disease progresses slowly, making it difficult to identify it at early stage. But the availability of potential therapeutic biomarkers in analysis and early identification of PD is of great importance. The current review discusses here the molecular biology, pathophysiology and availability of potential biomarkers associated with the PD condition.

Role of Reactive Oxygen Species in Neurodegenerative Diseases

The altered redox state leads to oxidative stress through the extravagant synthesis of reactive oxygen species (ROS) and inhibition of the antioxidant system. The high oxygen demand in nervous tissue makes it vulnerable to ROS, and the presence of peroxidation-prone lipid cells worsens the situation. We now understand that oxidative stress plays a role in the pathophysiology of neurodegenerative diseases such as Parkinson's disease, Motor neuron disease, and Alzheimer's disease. In spite of the fact that there is no lasting cure for any of these diseases, antioxidant treatments have been promoted as ways to treat and discourse neurodegenerative diseases. However, the results regarding their efficacy are contradictory. This chapter examines the role played by oxidative stress in the etiology of neurodegenerative diseases and how they lead to brain dysfunction in people. It will later provide an overview of antioxidants as a therapeutic option for oxidative stress-induced damage.

Neurodegenerative Diseases Involve Multifactorial Interplay of Genetics and Environmental Factors

Neurodegenerative diseases are one of the leading causes of morbidity and disability worldwide, afflicting millions of individuals. These diseases emerge as a result of multiple factors, sharing pathogenic pathway that includes mitochondrial dysfunction, misfolded protein aggregation, and oxidative stress. Genetic and environmental factors have been identified to play a key role in neurodegeneration and modifying the risk of the disease. The association of neurodegenerative diseases to genetic factors and environmental agent’s exposure is not well conclusive. As a consequence, studying the interplay of genetic and environmental factors in neurodegenerative diseases can help researchers better understand gene and therapy and disease progression. In this chapter, an attempt has been made to discuss the multifactorial degenerative process and the role of genetic and environmental factors in common neurodegenerative diseases. Understanding the mechanisms of disease initiation and progression is crucial for disease prevention and modification of disease risk. These information would be helpful in the exploration of therapeutic options against these diseases.

Lung Cancer Diagnosis: Where we are and where we will Go? Classical and Innovative Applications in the Diagnosis of Lung Cancer

Lung cancer is the leading cause of cancer death in both men and women

and is the second most common type in both. It generally has a poor prognosis, with 75

percent of patients being diagnosed at an advanced stage. The diagnostic tools typically

in use are insufficiently sensitive and do not allow for early disease detection. As a

result, finding alternative ways of early and accurate lung cancer diagnosis is critical

for successful management. CT imaging, sputum cytology, biopsy, and bronchoscopy

are examples of traditional procedures that have been adjusted over time to improve

sensitivity and accuracy. Lung biopsy is a reliable procedure performed to help define

the treatment strategy for patients with lung cancer. The use of computed tomography

(CT), EBUS, EUS and bronchoscopy allowed the collection of specimens for a greater

number of patients through minimally invasive procedures. The recent advances in

molecular technologies and analytic platforms have made it possible to investigate the

gene variations that contribute to tumorigenesis and become potential lung cancer

biomarkers. Furthermore, liquid biopsies tend to be a safe alternative to traditional

biopsies and can offer both accurate molecular data and a less invasive method of

evaluating tumor activity, which could further improve the clinical management of

lung cancer patients. This chapter provides an overview of the different traditional and

emerging diagnostic tools for lung cancer. We need to understand the characteristics of

these procedures that could have predictive, prognostic and therapeutic implications.

Physiological Basis for the Indication of Mechanical Ventilation

The respiratory system has a vital function in our body and several disorders

can cause Respiratory Insufficiency (RI). This disease, in turn, has an acute or chronic

form, as well as being classified as hypoxemic, hypercapnic and mixed. In addition,

there are three groups that cover the causes of RI, which are: hypoventilation,

impairment of diffusion and disturbances in the relationship between perfusion

ventilation. With regard to clinical manifestations, the respiratory system is affected by

this condition, from which the diagnosis of RI is made by blood gas analysis that

allows to differentiate it. In these cases, the patient is monitored by oximeters and

capnographs, the treatment being carried out by oxygen therapy and the use of invasive

and non-invasive mechanical ventilation.

Neuropathological Features of Covid-19

In December 2019, the world witnessed the spread of a new pandemic from the Wuhan city, China, which was later known as Coronavirus disease (COVID-19) caused by SARS-CoV-2. The main effects of Coronavirus disease (COVID-19) have been reported on human respiratory and cardiovascular systems, but neurological impacts have also been witnessed in most of the patients. Some common symptoms of COVID-19, such as stroke, anosmia, and dysregulation of breathing, are somehow related to the neuropathological processes. The detailed studies dealing with the neurological impacts of COVID-19 have revealed that the central nervous system is affected by SARS-CoV-2. Still, this disease also impacts the peripheral nervous system (PNS) and the muscles as well. T Guillain-Barré syndrome, Miller Fisher syndrome, polyneuritis cranialis, and viral myopathy with rhabdomyolysis are some of the diseasesthat affect muscles and the peripheral nervous system (PNS), but these diseases are usually less frequent. Usually, the symptoms of Coronavirus disease (COVID-19) impacting the neurological system are reported in cases of severe illness. Thus care must be taken during the treatment of Coronavirus (COVID-19) patients. A careful diagnosis is key before starting the treatment. This chapter aims to discuss the neuropathological impacts of the infection caused by SARS-CoV-2.

Magnetic Nanoparticles for Imaging, Diagnosis, and Drug-Delivery Applications

Magnetic Nanoparticles (MNPs) have gained interest within the research community due to their therapeutic potential in a variety of medical applications. MNPs are generally composed of a metallic core stabilized by the addition of an outer shell that can be further functionalized through the absorbance or conjugation of various targeting ligands. The magnetic properties of these nanoparticles can be utilized for imaging, localized drug delivery, and enhanced diagnostic detection. This chapter highlights the applications of MNPs to enhance magnetic resonance imaging (MRI) capabilities and improve the delivery of therapeutic agents to difficult-to-reach areas in the body. In addition, recent advances in the use of MNPs in stem cell therapy for both the tracking and monitoring of stem cell distribution in the body and improving engraftment and differentiation in stem cell therapy are discussed. Finally, examples of the incorporation of MNPs in diagnostic assays to improve rapid and realtime detection capabilities of many diseases, including cancer, cardiovascular diseases, and pathogen infections, are provided.

Anesthesia for Uncommon Pediatric Diseases

Several uncommon pediatric diseases encountered by non-pediatric anesthesiologists bear discussion because a failure to recognize unique issues relating to them could lead to significant morbidity and mortality. Anterior mediastinal masses share the same space as major pulmonary and cardiovascular structures, which, if compressed, can compromise the airway, heart and great vessels. Awareness of the potential for major physiologic derangement and a multidisciplinary approach to their diagnosis and management will ensure a safe perioperative course. Congenital pulmonary airway malformation is one of the most frequent pulmonary malformations in children that requires surgical intervention by thoracoscopic approach in the first year of life. Their anesthetic management is often challenging due to their small size, need for lung isolation and maintaining adequate oxygenation during surgery. Understanding lung isolation technique in infants is necessary for the safe administration of anesthetics in these children. Arthrogryposis multiplex congenita syndrome is a rare, non-progressive, and congenital heterogeneous group of disorders characterized by congenital joint contractures. These children require frequent surgeries during childhood to address various musculoskeletal abnormalities. Their anesthetic management is often challenging due to comorbidities related to musculoskeletal deformities, neurologic, cardiovascular and respiratory systems involvement. Understanding the disease with thorough evaluation and preparation prior to anesthetic management is essential for a good perioperative outcome. Pheochromocytoma is a rare neuroendocrine tumor in children that may present unexpectedly for the management by anesthesiologists. It secretes catecholamines which can cause lifethreatening perioperative hemodynamic instability. The meticulous preoperative pharmacotherapy, intraoperative anesthetic management and postoperative monitoring are vital for a safe outcome.

Pediatric Pain Management and Regional Anesthesia

Inadequate pain management in children not only leads to immediate stress and suffering, but it can also influence long-term psychological, physiological, and emotional outcomes for the patient and family. It is well-established that neonates not only feel pain, but also have an exaggerated perception due to immaturity of the descending inhibitory pathways. In addition, various physiologic differences influence the effect and duration of various medications. Despite the existence of many validated tools and pain scales, the assessment of pain in children is challenging. Successful acute pain management targets various elements in the complex system of pain transduction, transmission, modulation, and perception. A multimodal approach targeting multiple steps in the nociceptive pathway is more effective than those involving a single target. Regional analgesic techniques supplemented with opiates and nonopioid medications have proven to be effective in controlling postoperative pain. Traditionally, caudal and epidural analgesia have an established record of safety and are popular regional techniques in children. However, advances in ultrasound-guided techniques have encouraged pediatric anesthesiologists to perform more regional blocks in children. Additionally, application of the enhanced recovery after surgery (ERAS) protocol for major surgeries and concern about the opioid epidemic has led to increasing awareness about the benefits of regional anesthesia. In this chapter, we will discuss the fundamentals of pain perception in children, the assessment of pain and the multimodal approach to manage it, relevant pharmacology, and various regional techniques in routine and complex pediatric surgical patients.

Anesthesia for Pediatric Patients with Common Comorbidities Part III

There have been dramatic improvements in the survival of neonates and children with many diseases and disorders due to advancements in medicine over the past several decades. These advances are attributed to the better understanding of these disease processes, the advent of multidrug combinations, molecularly targeted therapies, critical care and various surgical interventions. In the wake of this rapidly developing wide range of treatment protocols, the anesthesiologist needs to have a clear understanding of these disorders and their comorbidities, and stay abreast of the various treatment modalities, including their safety and toxicity profiles. This review attempts to emphasize some of the clinical conditions unique to these patients and special considerations for the conduct of anesthesia in this population. Some of the disease processes and comorbidities discussed here include anesthetic considerations for ex-premature infants, diabetes mellitus, obesity, childhood cancer, and children with congenital heart disease who present for non-cardiac surgery. The objective of this discussion is to provide an updated and comprehensive review of current perioperative anesthetic management of pediatric patients with these conditions. We also delineate the effects of anesthesia during the perioperative course, including major metabolic changes that may result in increased morbidity. We provide guidelines for any anesthesia provider involved in the care of these vulnerable patients. Special considerations need to be taken to promote the physical and mental wellbeing of these children and their families. Collaborative coordination with all providers involved in care is essential to provide safe and effective anesthesia to this subset of patients.

Subject Index

Updates on Mitochondrial Disorders in Children

Each human cell contains a few hundred mitochondria that are essential for aerobic energy metabolism. Among many fundamental metabolic pathways in mitochondria, the oxidative phosphorylation (OXPHOS) or the respiratory chain (RC) represents the final stage in oxidative metabolism. RC is under the dual control of the mitochondrial genome (mtDNA) and the nuclear genome (nDNA). The proper assembly and functioning of the RC involve many steps. The genetic defects in mtDNA, nDNA, and related functions of mitochondria affect the functioning of RC resulting in insufficient energy production and organ dysfunction. Mitochondrial disorders are increasingly recognized. The clinical manifestations vary widely, causing a significant diagnostic challenge. Manifestations range from lesions of single tissue or structure to widespread lesions, including myopathies, encephalomyopathies, cardiopathies, neurogastrointestinal form, psychiatric symptoms, or complex multisystem syndromes. Coenzyme Q10 deficiency may present with isolated proximal muscle weakness. Leigh syndrome and MELAS are the most common clinical multisystem syndromes. The age at onset ranges from neonatal to adult life. The mortality remains high, and the median survival for early onset severe disease is 12years. Initial evaluations include blood transaminases, lactate-to-pyruvate ratio, amino acids, acylcarnitine profile, creatine kinase, and organic acids. Genetic tests are needed for confirmation. Treatment depends on the specific mitochondrial disorder and its severity. In an acute presentation, an infection should be sought and treated promptly. Coenzyme Q10, thiamine, riboflavin, lipoic acid, L-carnitine, Creatine, and L-Arginine are found to be beneficial. Although there are no cures, treatments reduce symptoms or slow the decline in health.

Updates on Pediatric Demyelinating Disorders

Myelin is a protective layer that enwraps the axonal terminals and is an essential component of the central nervous system white matter. Loss of myelin leads to conduction block in the axon leading to demyelinating disorders. Inherited poor formation of myelin is known as hypomyelination, and abnormally formed myelin is called dysmyelination. Demyelinating disorders exclude diseases where degeneration of the axon is the initial event and myelin is degraded secondarily. Most neurologists use the term demyelination only for acquired forms of loss of myelin with relative preservations of axons due to inflammation such as multiple sclerosis. Demyelinating disease in children may be monophasic (e.g., acute disseminated encephalomyelitis, optic neuritis, and transverse myelitis) or chronic (multiple sclerosis and neuromyelitis optica). Pediatric multiple sclerosis is the most common demyelinating disorder in children. Recent genetic and clinical researches have significantly improved our understanding of the diverse spectrum of pediatric demyelinating disorders. In this chapter, an updated summary of the current knowledge on the categories, diagnosis, as well as management of pediatric demyelinating disorders has been presented.

Introduction of Common Pediatric Diseases

Pediatric health has improved over the past decades and there is a decline in deaths caused by infectious diseases. Yet, the top three causes of disease in children younger than 10 years in 2019 include neonatal disorders, lower respiratory tract infections, and diarrheal diseases. While in the adolescence age group, the major causes are road injuries, headache disorders, and self-harm. Preterm birth complications, pneumonia, and birth asphyxia are the most leading cause of death in children under five years. While in the five to nine years of age group, injuries, including road traffic injuries, drowning, burns, and falls, are the leading causes of death.

A Review of the Impact of Testosterone on Brain and Aging-related Decline in Brain Behavioural Function

The hormone testosterone is known to affect a variety of functions in the

body, a number of which are related to behaviour, and preservation of brain neuronal

integrity. Along this line, certain experimental evidences suggest that testosterone

supplementation may be beneficial in the preservation of cognitive functions and

neuronal integrity in aging and may be a valuable addition to a growing arsenal of

medications that can be used to combat aging-related cognitive decline. However, some

other studies have suggested instances where testosterone supplementation may be

deleterious for the brain neurons, while under certain conditions, the likely effects of

testosterone supplement may not be clear. Some studies had even suggested that race

may be a major determinant of testosterone’s effects on the brain. In this review, salient

aspects of testosterone’s effects on the brain are discussed with emphasis on its

behavioural and morphological effects. The impacts of aging on the behavioural and

brain morphological effects of testosterone are also discussed, with emphasis on its

nootropic effects. The limitations to the clinical application of testosterone in

mitigating aging related cognitive decline are also considered.

Modulation of Mesenchymal Stem Cells, Glial Cells and the Immune System by Oligodeoxynucleotides as a Novel Multi-target Therapeutic Approach Against Chronic Pain

Despite our growing understanding of chronic pain mechanisms, an

alarming proportion of patients worldwide remains refractory to treatment. Chronic

pain is complex, involving the interaction of both neuronal and non-neuronal systems.

Several studies focused on immune, glial and mesenchymal stem cells (MSCs) have

recently revealed key roles of these non-neuronal players in the initiation and

perpetuation of chronic pain. The complexity of chronic pain is reflected by the

difficulty of its therapeutic control, in particular when using mono-target drugs. A good

proportion of these drugs target neuronal pathways, and serious concerns arise when it

comes to the use of opioids and abuse liability. In contrast, novel pain drugs targeting

non-neuronal components of chronic pain are scarce. Exceptions include classical nonsteroidal

anti-inflammatory drugs, or those modulating trophic factors, although their

use remains restricted to the presence of appropriate targets. Synthetic

oligodeoxynucleotides have been used as immune system modulators for the last 15

years. One of them, IMT504, a non-CpG oligodeoxynucleotide, exhibits remarkable,

long-lasting anti-allodynic and anti-inflammatory properties upon single-dose systemic

administration in rodent models of inflammatory or neuropathic pain. Mounting

evidence suggests that the beneficial effects of IMT504 relate to actions on the immune

system, glial cells and MSCs. In this state-of-the-art chapter, we address the current

knowledge of the role of IMT504 over non-neuronal cells, its impact on chronic pain,

and its translational potential. We also propose that further analysis on its mechanisms

of action will be key to the identification of novel and effective multi-target pain drugs

without abuse liability.

Neurotrophic Factors to Combat Neurodegeneration

Conditions caused by the lesion and progressive death of neuronal cells in

the organism include neurodegenerative disorders and neuropathic pain. They represent

the major causes of disability in Western countries. These conditions are more common

in elderly people, and their prevalence, therefore, is expected to grow in the future

because of the aging population. Currently, curative therapies against

neurodegenerative disorders and neuropathic pain are not available. Existing treatments

may provide temporary symptomatic relief to some patients but fail to stop neuronal

degeneration, protect and restore damaged neurons. Neurotrophic factors are small

secretory proteins whose main function is to support the survival of neurons. Therefore,

they hold considerable promise for disease-modifying treatment of neurodegenerative

disorders and neuropathic pain. However, despite promising results in preclinical

studies, clinical translation of neurotrophic factors has so far achieved limited success.

Neurotrophic factors are different from traditional chemical compounds used as drugs

in the majority of cases, and this complicates their clinical use. Biology of neurotrophic

factors and their absorption, distribution, metabolism, excretion, and pharmacokinetics

properties dictate special requirements to clinical trials design. Patients taking part in

clinical trials, delivery system, delivery paradigm, and the dose of neurotrophic factor

should be carefully considered in trial design in order to ensure that the treatment will

improve the condition of patients.

In the present chapter, the author summarizes the available literature regarding

signaling of neurotrophic factors, provides the data about their preclinical evaluation in

animal models of neurodegenerative disorders and neuropathic pain, describes the

results of clinical trials conducted with neurotrophic factors in patients, and discusses

the limitations of these trials and translational problems faced by researchers and

clinicians in this field. The author will further discuss emerging alternatives to

neurotrophic factor proteins with improved translational perspectives, such as mutant

proteins, small molecules, and peptides targeting the receptors of neurotrophic factors.

The author will review attempts of clinical translation of glial cell line-derived

neurotrophic factor family ligands for the treatment of Parkinson’s disease and

neuropathic pain. The author will briefly describe the non-conventional cerebral

dopamine neurotrophic factor tested in Phase I/II clinical trial in patients with
Parkinson’s disease. The author will also describe the data concerning the clinical evaluation

of other neurotrophic factors in the above-mentioned conditions.

The Cell: The Basic Functional Unit of Life

Cell is the smallest and the basic functional unit of life. Every organism,

whether prokaryotic, archaeans, or eukaryotic, is composed of a basic building block

which is the Cell. A cell consists of a cell membrane, a nucleus, and a cytoplasm where

intricate arrangements of fine fibers and organelles lie. Cells are specialized for a

specific purpose, they form tissues which in turn form organs, and several organs make

up the system, and several systems that function together form the organism. The

present chapter aims to describe the body, tissues, system, organism, and the structure

and function of the major cell organelles with a focus on eukaryotic cells.

From Cells to Clinic - Direct Biomolecule Quantification of Clinically Relevant Biomolecules

Translation of investigative cellular analysis into reliable clinical settings is

a challenge and surface enhanced Raman spectroscopic (SERS) technique has the

potential to move beyond laboratorial examinations. Quantitative and qualitative

measurement of cellular components and their properties is essential indicative of

healthy or disease state. Pre-emptive analysis of diseased state offers synchronization

with early diagnosis of certain medical conditions and is requisite for initiation of

therapeutic interventions. High sensitivity and capacity for multiplexing renders SERS

suitable for biochemical analysis for disease diagnosis a critical step towards

formulation of therapeutic regime. SERS assists in a deeper understanding of cellular

processes and its micro environment without disturbing and damaging the cellular

milieu in 3 dimensional (3D) set up without invading the tissues. Fabrication of novel

nanostructures with enhanced plasmonic effects has also propelled the growth of SERS

based analysis of cellular structure in normal and abnormal circumstances. Thus, SERS

is operating as diagnostic tool for in-vitro, ex-vivo and in-vivo investigations for

assessing onset of disease as well as prognosis of the therapy in hospitals and clinics.

Recent Updates in the Animal Models of Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory, autoimmune disease characterized by neuronal demyelination of the Central Nervous System (CNS). It affects more than 2 million people worldwide. Animal models are of great importance in elucidating immune-pathological mechanisms of MS. The three most commonly studied categories of MS animal models are (1) the Experimental Autoimmune Encephalomyelitis (EAE); (2) chronic demyelinating disease models through virus inoculation known as Theiler's Murine Encephalomyelitis Virus (TMEV) infection and (3) toxin-induced models of demyelination, comprising the focal toxin-induced demyelination by lysolecithin (lysophosphatidylcholine), ethidium bromide, antigalactocerebroside (GaIC) antibody) and systemic toxin-induced demyelination by cuprizone. EAE is a widely accepted animal model that reflects the pathological mechanisms of MS, making it highly useful to analyze new therapeutic approaches. However, TMEV infection and toxin-induced models are most suitable for studying the role of de and remyelination processes and axonal injury or repair in MS. Furthermore, Zebrafish models have also emerged in recent years as novel animal models for MS because of their swift development and controllable genetic manipulations. In a nutshell, despite their limitations, animal models remain the most useful research tools to answer specific research questions related to pathological mechanisms and to validate potential experimental therapies for MS.

Aluminium and other Metals Exposure Cause Neurological Disorders: Evidence from Clinical/ human Studies

Exposure to Aluminium and other heavy metals has become a serious concern in today’s modern life. Due to excessive use and improper disposal of heavy metals, the entire food chain is being contaminated, which is imposing various health risks for humans and other living organisms. These heavy metals particularly induce oxidative stress through different mechanisms which can ultimately interfere with the normal physiological activities. Brain is highly prone to oxidative stress due to its rich polyunsaturated content and high oxygen consumption than the periphery. Therefore, emphasis has been given to neurotoxicological effects produced by exposure to heavy metals. In this regard, the effects of both essential and non-essential heavy metals have been investigated in various clinical studies which are demonstrating them as a serious threat to normal brain function. This chapter summarizes the neurotoxicological effects of heavy metals which have been revealed in various human studies.

Gene Therapy and Editing for the Treatment of Single-Gene Pain Disorders

It is a well-known reality that genetic variants can alter the pain perception of an individual in correlation with painless and painful voltage-gated Nachannelopathies for the better understanding of molecular transmission and detection events to noxious stimuli. Mutations in Nav 1.7 gene coding for the Na-ion channel can cause severe syndromes of distinctive pain such as small-fiber neuropathy, inherited erythromelalgia, and paroxysmal pain disorder. Whereas the inactivation of SCN9A mutations that encodes Nav 1.7, as a consequence, leads to insensitivity to pain congenitally. The TRPA1 heterozygous mutations code for Nav1.9 (SCN11A) and Nav1.8 (SCN10A) can cause insensitivity to pain while other variants are responsible for the potential-cation channel of the transient-receptor which can cause episodes of familial pain syndromes. Moreover, recently found few other novel genetic polymorphisms essentially identify the severity and complexity of the pain phenotypes. Various pain models for a better understanding of the sensory disorders and heritable disorders of pain are in the developmental phase. Therefore, devising new therapeutic approaches, genome-guided therapy, and understanding the structure of receptors for novel drug development and delivery in correlation with Na-ion channel is imminent.

Monoclonal Antibodies as Therapeutic Agents for Inflammatory Diseases

Inflammation is a physiological process caused when an agent (chemical, biological or physical) transcends the primary defense barrier of an organism, setting a series of biological reactions to restore the integrity of such organism, thus playing a central role in the fight against those pathogens. Uncontrolled amplification of these events may lead to undesirable pathological manifestations such as cancer, diabetes, and cardiovascular, neurological, and chronic inflammatory diseases. Monoclonal antibodies (mAbs) were first described in 1975, and since then, they have proven to be relevant therapeutic agents in a myriad of diseases. The US Food and Drug Administration (FDA) has already approved more than 90 mAbs for the treatment of several diseases, from which approximately 26% were specifically approved for the treatment of inflammatory diseases, for instance, rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, and palmoplantar pustulosis. This chapter provides an overview of the inflammation process and main biochemical mechanisms, together with a vision on the current state of the art of the mAbs-based biopharmaceuticals market and their application as powerful therapeutic agents for inflammatory diseases.

Comorbidities Inducing Mild Cognitive Impairment, an Evaluation of the Risk Caused by some Pathological Conditions

Mild cognitive impairment has usually been associated with aging, however, in recent decades with the increase in the prevalence of pathologies such as obesity, diabetes mellitus, cardiovascular diseases, and even spinal cord injury, it has become evident that a significant percentage of people who suffer from one or more of these diseases are at greater risk of suffering from some level of cognitive impairment that can lead to the development of various types of dementia. In this chapter, we review the main characteristics and mechanisms that promote the development of this type of alteration in each of the mentioned pathologies and briefly describe the various ways in which they have been approached.